challenges and opportunities in developing and modernizing ...april 28-29, 2015 challenges and...
TRANSCRIPT
1
Catherine SheehanSr. Director, Excipients United States Pharmacopeial Convention
Excipient Fest Puerto RicoApril 28-29, 2015
Challenges And Opportunities In Developing And Modernizing Public Standards For NF Monographs
• Overview of the U.S. Pharmacopeial Convention (USP)
• How USP Standards are Established through a Public Process
• Call for Candidates: 2015-2020 Council of Experts
• USP-NF Up to Date : overview of the USP Modernization Initiative
• Excipient Modernization – progress
• Summary
2
Presentation Outline
2
USP – An Overview
US Pharmacopeial Convention (USP) founded in 1820. USP is a scientific, nonprofit, nongovernmental, private, independent, and self-funded organization
2015 USP is headquartered in Rockville, MD; 800+ employees; facilities in India, China, Switzerland, Brazil, Ghana and Ethiopia
USP is cited in United States Law…
1848: Drug Import Act
1906: Pure Food and Drug Act
1938: Federal Food, Drug and Cosmetic Act (FFD&C Act)
– Definition of a drug
– Adulteration
– Misbranding
– Drug product name
1994: Dietary Supplement Health and Education Act (DSHEA)
2003: Model Guidelines for Medicare Formularies
• In the FFD&C Act, both United States Pharmacopeia (USP) and the National Formulary (NF) are recognized as official compendia for drugs marketed in the United States. The USP-NF is two separate books published as one compendium.
USP – An Overview
3
The United States Pharmacopeia and the National Formulary (USP–NF)
– Published annually with 2 supplements.
Food Chemicals Codex
USP Dietary Supplements Compendium
Reference Standards
Other Resources
– Pharmacopeial Forum
– FCC Forum
– USP Dictionary
Core Compendial Programs
Pharmacopeial Forum and FCC Forum
USP’s vehicles for public notice and comment
PF a free online-only service as of January 2011
Includes an archive back to PF 28 (2002)
FCC Forum online only
Contents– Interim Revision Announcements
(PF Only)
– In-process Revision
– Stimuli to the Revision Process
– Nomenclature
– Harmonization
4
USP creates and continuously revises USP–NF standards through a unique public–private collaborative process
This involves scientists in industry, academia, and government as well as other interested parties from anywhere in the world.
Public input and interaction are vital to the development of USP standards.
The standards generally originate from sponsors who provide draft standards and supporting data to either create new or revise (modernization) existing monographs and general chapters.
Standards Established through a Public Process
USP's scientific staff and volunteer experts review sponsor’s input, conduct laboratory tests (if necessary), and publish the proposed new or revised monograph or general chapter inthe Pharmacopeial Forum (PF) for public review and comment.
The public comment process helps to refine USP standards for publication as official text in the USP–NF.
Prior to publication as official text, all USP-NF monographs and general chapter proposals must be approved by a USP Expert Committee (EC).
EC is comprised of volunteer scientists, academicians, practitioners, and other professionals elected on the basis of their knowledge and expertise.
http://www.usp.org/usp-nf/pharmacopeial-forum
Standards Established through a Public Process
5
Expert Committee Role in Standards-setting Processes
• Work with Scientific Liaisons and Reference Standard Scientists
• Evaluate all input and comments (from the public, Expert Panel, staff, etc.)
• Decide whether to incorporate comments into the final text without republishing for public review or if additional public review is needed before revision is adopted
• Vote to adopt official/effective/authorized text
• Approve monograph and general chapter text and the use(s) of USP Reference Standards in the monograph or general chapter
• Maintain confidentiality of standards-setting documents, information and activities
• Declare conflicts of interest
Seeking experts in pharmaceutical, biological, and food sciences; pharmacy; medicine; and related disciplines to volunteer for USP’s Council of Experts and Expert Committees for the 2015-2020 cycle
Application deadlines: May 15, 2015: Expert Committee members
May 27-28, 2015: CoE Orientation and Election of Expert Committee members
July 2015: 2015-2020 Council of Experts and Expert Committees begin their work
Visit https://callforcandidates.usp.org/node and click the Call for Candidates banner to access information and to create an application account.
Call for Candidates: 2015-2020 Council of Experts
6
USP Expert Committee Member Application Process
USP Expert Committee Member Application Process
7
USP collaborated with FDA and excipient stakeholders (users, makers, and distributors) to modernize excipient monographs.
To date, 62 monograph identification, 30 assay, 11 impurity tests and a General Chapter <1197> Good Distribution Practices for excipients were developed.
The new compendial quality specifications and general chapters help improve testing controls and provide tools to qualify an excipient for intended use.
13
2010-2015 Excipient Expert Committee achievements
8
2015-2020 Excipient Expert Committees
Exc
ipie
nt M
onog
raph
s 1 EXC A Subcommittee (SC)
Small molecules
EXC B SC
(Polymers, Proteins, Clays)
EXC C SC
(Oils, Fats, Waxes, Plants)
EXC-B&B Cross Cutting Subcommittee (CCSC)
General Chapters CCSC Exc
ipie
nt M
onog
raph
s2 PDG Monographs
8 Subcommittees (SC)
(D-K)
PDG General ChaptersCross Cutting Subcommittee
(CCSC)
Bilateral Harmonization SC
Prospective Harmonization SC
Excipient Monograph Collaborative EC
Expert Panels on <1059> and <1197> Expert Panel on Talc, Glycerin and Povidones
New monograph development with associated RS
Monograph modernization with associated RS
New excipient related chapters development
Excipient General Chapters update
International harmonization
–PDG
–Bilateral harmonization
–Prospective harmonization of API, DP & Excipients
16
Focus Areas for 2015-2020 revision cycle
9
USP has resolved to bring its compendia, the United States Pharmacopeia—National Formulary (USP–NF), up to date by 2020.
The objective of this initiative is to develop standards that reflect “state-of-the-industry” techniques for sufficiently monitoring drug quality, purity, and strength.
This includes an effort to ensure that all monographs in the USP–NF —including those for chemical medicines, excipients, and biologics—are current, relevant, and suitable for their intended use.
USP–NF Up to Date by 2020
• USP has made tremendous progress in modernizing outdated methodologies in the USP–NF through collaborative efforts with FDA and its stakeholders.
• Modernization of Heparin, Glycerin and Acetaminophen are examples of USP, FDA, and industry working together to enhance global health through the improvement of public quality standards.
• USP’s intensified focus on updating USP–NF is expected to result in an increase in monograph proposals over the next five years.
• USP’s outreach to stakeholders will be proactive; encourage industry to contact USP in this effort.
• USP will dedicate additional resources and optimize its internal processes to successfully accomplish this goal by 2020.
What is meant by USP–NF “up to date”?
10
Primary driver is maintaining up-to-date quality standards to support USP’s commitment to public health
Need for modernization Monographs have been official for several years, decades in some
cases and have not kept pace with scientific advancements
Content does not reflect current expectations for scientific procedures and acceptance criteria
Complaints from stakeholders
General lack of specificity
Unsafe or use of hazardous materials
Modernization is a subset of USP’s ongoing revision work, started using the term “modernization” in 2009
USP Monograph Modernization Initiative
Benefits Strengthens USP public standards to current pharmaceutical
practices
Moves from non-specific to specific procedures
Considers practical factors – removes unnecessary and outdated tests
– Safety/environmental issues considered such as eliminating use of chlorinated solvents
– hard to find equipment that is no longer available
Increases consistency across monographs
USP Monograph Modernization Initiative
11
Approaches to monograph and reference material procurement and
development:
Traditional donor model (‘externally sourced’)
– Very difficult to engage sponsors
USP laboratories (‘internally sourced’)
– Extensive testing facilities for procedure development
– Collaborative testing sites in US, India, China and Brazil
FDA (CRADA: ORA Labs)
Expert panels to leverage industry expertise, gain early stakeholder input and buy-in
Adapt/Adopt (Other Pharmacopeias e.g. E.P., J.P., B.P., ChP, etc.)
– Identify alternate source procedures (i.e., procedures that can be used from other pharmacopeias)
– In some cases, the alternate source procedure for one test (e.g., Impurities) may be the starting point for an R&D lab project for modernization of another test (e.g., Assay)
Monograph Modernization Strategies
USPAnalytical
Laboratories
USP Global Laboratory Capabilities
43,000 sq.ft
65,000 sq.ft.6,400 sq.ft
53,000 sq.ft.
12
Modernization of monographs achieved by
– Replacing outdated technology and methodology with more current procedures
– Adding critical tests to the monograph
– Deleting non-value added tests, as needed (e.g., odor test, melting point)
Follows the USP standards-setting process (i.e., with publication in PF for 90-day comment period)
FDA to provide input to USP on prioritization of excipients (FDA MMTG and ORA lists) in the U.S.
Other considerations
–Use procedures from other pharmacopeias–May need RS materials –Revising the monograph “family”, as needed
USP Monograph Modernization Process
No Identification or non-specific Identification procedures
No Assay or non-specific Assay procedures
– Stainless steel/packed column GC procedures
– Titration to GC/HPLC where appropriate
No impurity test, (e.g., Povidones and peroxides/aldehydes)
Safety-related concerns (e.g., chlorinated solvents).
Additional requirements
Monograph Labeling deficiencies , e.g., when used in parenteral/injectable applications (Fit for Purpose)
Missing specific tests to control quality (e.g., Microbial/BE)
Excipient Monograph Modernization: Prioritization of Categories
13
FDA Modernization Task Group (MMTG) Nov. 2010
MMTG was established within the FDA Pharmaceutical Quality Standards Working Group
– Concern that USP-NF excipients at an elevated risk of adulteration because of a lack of specificity of the Identification test.
– Total of 19 high priority excipients including ORA list of 4
– List includes USP-NF excipient monographs in the Pharmacopeial Discussion Group (PDG) work program.
Modernization initiative is helping USP as the lead/coordinating pharmacopoeia in approaching steps 1-3 of the PDG process.
USP has began to convene global Expert Panels for PDG related excipient monographs to ensure that the standard is agreed upon by global experts prior to PDG discussion. (Talc, Povidones and Glycerin)
USP Monograph Modernization - Excipients
USP Monograph Modernization - Excipients
14
FDA MMTG/ORA lists of Priority Excipient NF Monographs in need of modernization
http://www.usp.org/usp‐nf/key‐issues/monograph‐modernizationMonograph List FDA Recommend PF for comment /Status
Povidone (H)
Crospovidone (H)
Copovidone (H)
MMTG Replace non‐specific N determination Assay
<461> Kjeldahl method. Add Peroxide test
PDG S6 – Add ID by IR,
add Impurities tests ‐
Peroxide, hydrazine
Talc (H) MMTG Revise Limit of Asbestos. Update Definition &
Labeling
PF 40(4)‐Stim article
Butylated Hydroxyanisole MMTG Lack of specific ID PF40(6)
Butylated Hydroxytoluene MMTG Lack of specific ID PF 40(2)
Calcium Stearate MMTG Lack of specific ID PF 39(4)
Croscarmellose Sodium (H) MMTG Lack of specific ID in development
Carboxymethylcellulose Sodium (H) MMTG Lack of specific ID in development
Dextrose (H) MMTG Lack of specific ID in development
Gelatin (H) MMTG Lack of specific ID PDG Stage 6 official
Guar Gum MMTG Lack of specific ID PF 39(5)
Microcrystalline Cellulose (MCC) (H) MMTG Lack of specific ID Target PF 41 (5)
Pregelatinized Starch MMTG Lack of specific ID in development
Shellac MMTG Lack of specific ID PF40(4)
Silicon Dioxide (Colloidal) (H) MMTG Lack of specific ID in development
Titanium Dioxide (H) MMTG Lack of specific ID in development
Gelatin (H) MMTG Lack of specific ID in development
Aspartame ORA Replace nonspecific assay titration ; add impurities test PF40(4)
Glycerin (H) ORA Assay method for glycerin is out of date (periodate
method)in development
Titanium Dioxide (H) ORA Assay method is out of date, involves digestion with
concentrated acids.in development
Crospovidone (H) ORA Test method for Peroxides is outdated in development
The USP Excipient (Exc) Expert Committee has created 3 Expert Panels
to address FDA’s request to modernize 3 excipient monographs for
Glycerin (S3), Talc (S6) and Povidones (Povidone (S6), Crospovidone
(S6) and Copovidone (S4) ).
These monographs are also part of the Pharmacopeial Discussion Group’s
workplan.
Expert Panels allow for global participation of excipient users, makers,
distributors, governmental and academics in method development and
testing that provide recommendations to the Exc Expert Committee.
Aim is to submit EP’s/Exc EC proposed methods to PDG for
consideration in the development of a harmonized PDG monograph.
Talc EP published a stimulus article in PF 40 (4) on the revision of the
Test for “Absence of asbestos”. USP still accepting comments on the
article. ( email Kevin Moore at [email protected] )
USP Expert Panels (EP) supporting Modernization
28
15
Case StudyModernization and Harmonization of Cellulose-based Excipient MonographsMicrocrystalline Cellulose (MCC), Carboxymethylcellulose Sodium (CMC Na) and Croscarmellose Sodium (CROS Na)
The FDA MMTG identified several cellulose-based excipient monographs as high priority for modernization that may be at an elevated risk of adulteration due to a lack of specificity of the Identification (ID) test.
Microcrystalline Cellulose (MCC), Carboxymethylcellulose Sodium (CMC Na) and Croscarmellose Sodium (CROS Na)
Develop a compendial ID to establish identity; also be specific and discriminate compounds of closely related structure, such as
MCC, CMC Na and CROS Na, hydroxypropyl cellulose (HPC) and low-substituted hydroxypropyl cellulose (LS-HPC), hypromellose (HMPC), etc.
Under CGMP regulations, pharmaceutical drug manufacturers must perform at least one test to verify the identity of all component ingredients used to make the finished drug product and, where available, the compendial identity test is often used.
Modernization of Identification for Cellulose-based Excipient Monographs
16
For some excipients, one ID test may not suffice
May be necessary to include orthogonal test(s) under the Identification.
Challenges exist in developing compendial specifications for cellulose-based excipients
known variability based on grade (i.e. degree of polymerization, particle size, solubility, etc.), manufacturer’s processing parameters (site, processing, potential mixtures/additives) and raw material origin.
The EXC EC began by implementing a comprehensive approach to develop specific ID tests for these chemically-similar cellulose-based excipients based on infrared (IR) spectroscopy in combination with simple orthogonal methods.
Modernization of Identification for Cellulose-based Excipient Monographs
Eight monographs have ID by IR either official in the USP-NF monographs or proposed in Pharmacopeial Forum (PF), as shown in our USP Poster presentation, Table 1.
The EXC EC concluded that for chemically and structurally similar compounds, such as the Carmellose family (Carmellose, CMC Ca, CMC Na, and CROS Na), orthogonal tests, such as ion identification and/or solubility, may be necessary to distinguish the individual materials.
The USP staff and the EXC EC are currently reviewing the Identification section for the remaining seven cellulosic-based excipient monographs.
Stakeholders are encouraged to sponsor and submit methods/validation data to USP.
Modernization of Identification for Cellulose-based Excipient Monographs
17
USP’s Opportunities/Challenges to Modernization
• Challenges:• Obtaining procedures and acceptance criteria from sponsors
• With FDA involvement, prioritizing and requesting submissions -the hope is that industry is much more likely to submit a proposal.
• Opportunities:
• New approaches to modernization, especially use of USP China laboratory facilities to develop and validate procedures.
• Global expert panels and stakeholder collaborations can stimulate additional avenues for both modernization and harmonization.
• Sourcing procedures from other compendia, literature, etc.
► Excipient monograph modernization continues as a major initiative in the 2015-2020 CoE revision cycle. Monograph Modernization is critical given global supply chain threats
► 2 newly elected Excipient Monograph Expert Committees will continue the modernization initiative beginning in July 1, 2015
► Modernized excipient test methods helps to eliminate the opportunity to substitute or falsify excipient ingredients
► Obtaining samples, procedures and acceptance criteria from Sponsors is challenging
► Opportunities to collaborate with FDA, industry and other stakeholders is key to advancing the work
► Long-term goal is to implement a regular monograph review process to monitor the needs for further modernization
Summary
18
Upcoming Events for Excipients
http://www.usp.org/sites/default/files/usp_pdf/EN/excipients/newsletter/201502-newsletter.pdf?utm_source=iContact&utm_medium=email&utm_campaign=Excipients&utm_content=Excipients+e-news+template+201502
19